Submissions for variant NM_001035.3(RYR2):c.11497G>A (p.Asp3833Asn)

gnomAD frequency: 0.00003  dbSNP: rs768711283

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182796	SCV000235182	uncertain significance	not provided	2020-05-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified independently and in conjunction with additional cardiogenetic variants in individuals in published literature but segregation data are limited or absent at this time (Adler et al., 2016; Sahlin et al., 2019; Mademont-Soler et al., 2017); This variant is associated with the following publications: (PMID: 19926015, 26743238, 30615648, 28771489)
Invitae	RCV001099749	SCV000637481	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3833 of the RYR2 protein (p.Asp3833Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 26743238, 30615648, 32152366). ClinVar contains an entry for this variant (Variation ID: 201312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000778055	SCV000914170	uncertain significance	Cardiomyopathy	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 3833 of the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy who also carried a pathogenic variant in the MYBPC3 gene (PMID: 28771489). This variant has also been observed in an individual suspected of having inherited arrhythmia disease (PMID: 26743238) and in a stillbirth (PMID: 30615648). This variant has been identified in 9/195672 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001099749	SCV001256228	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001099750	SCV001256229	uncertain significance	Arrhythmogenic right ventricular dysplasia 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226238	SCV003922765	uncertain significance	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.11497G>A (p.Asp3833Asn) results in a conservative amino acid change located in the RyR/IP3R Homology associated domain (IPR013662) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 164282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11497G>A has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia (Adler_2016, Olubando_2020), hypertrophic cardiomyopathy (Mademont-Soler_2017), and stillbirth (Sahlin_2019) with conflicting interpretations of pathogenicity. These report(s) do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.